Objective To investigate the prognostic value of microRNA-122 (miR-122) combined with acute physiology and chronic health evaluationⅡ(APACHEⅡ) score in patient with acute respiratory distress syndrome (ARDS), and to provide evidence for the diagnosis and treatment of ARDS. Methods ARDS patients admitted to the Third People's Hospital of Haikou City from January 2016 to December 2018 were enrolled. The general data, serum miR-122 expression level and APACHEⅡ score within 24 hours were collected. The patients were divided into survival group and death group according to the survival status of ARDS patients. ARDS patients were divided into low-risk group ( < 10 scores), medium-risk group (10-20 scores) and high-risk group ( > 20 scores) according to APACHEⅡ score. Predictive values of miR-122 and APACHEⅡ scores on prognosis in ARDS patients were evaluated by the receiver operating characteristic (ROC) curve. The correlation between the serum miR-122 expression and APACHEⅡscore in patients with ARDS was calculated by Pearson correlation analysis. Results A total of 142 ARDS patients were selected, 94 male and 48 female; with age (56.80±11.30) years old; 55 deaths and 87 survivors; 67 of high-risk, 48 of medium-risk and 27 of low-risk. The expression of serum miR-122 and APACHEⅡ score in the death group were significantly higher than those in the survival group [miR-122 (2-ΔΔCt): 0.26±0.12 vs. 0.07±0.03, APACHEⅡ:31.84±4.25 vs. 15.30±2.60, both P < 0.01]. With the severity increase of the disease, the serum miR-122 expression level, APACHEⅡ score, and mortality rate of ARDS patients gradually elevated, and the difference between the two groups was significant in the low-risk group, medium-risk group, and high-risk group [miR-122 (2-ΔΔCt):0.05±0.02, 0.14±0.06, 0.23±0.09; APACHEⅡ: 12.30±2.15, 20.62±3.40, 28.90±3.60; mortality rate: 11.1%, 31.2%, 55.2%, respectively, all P < 0.05]. ROC curve analysis showed that miR-122 and APACHEⅡ score could predict the death of ARDS patients, and the area under the ROC curve (AUC) was 0.835 [95% confidence interval (95%CI) = 0.776-0.893] and 0.790 (95%CI = 0.732-0.854); the predicted value of the miR-122 combined with APACHEⅡscore (AUC = 0.918, 95%CI = 0.857-0.972) was higher than the single miR-122 and APACHEⅡscore (both P < 0.05), with sensitivity and specificity were 91.3% and 86.4% respectively. The correlation analysis showed that the expression of serum miR-122 was positively correlated with APACHEⅡscore in death patient with ARDS (r = 0.825, P < 0.01). Conclusion Elevated serum miR-122 expression level is associated with disease severity and prognosis of ARDS patients; miR-122 combination with APACHEⅡ score has a high evaluation value on prognosis of ARDS patients.